CN106389341B - Penfluridol polyanhydride pellet, penfluridol long-acting controlled-release tablet and preparation method thereof - Google Patents
Penfluridol polyanhydride pellet, penfluridol long-acting controlled-release tablet and preparation method thereof Download PDFInfo
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- CN106389341B CN106389341B CN201610804611.0A CN201610804611A CN106389341B CN 106389341 B CN106389341 B CN 106389341B CN 201610804611 A CN201610804611 A CN 201610804611A CN 106389341 B CN106389341 B CN 106389341B
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- penfluridol
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- release tablet
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- MDLAAYDRRZXJIF-UHFFFAOYSA-N 1-[4,4-bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol Chemical compound C1CC(O)(C=2C=C(C(Cl)=CC=2)C(F)(F)F)CCN1CCCC(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 MDLAAYDRRZXJIF-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 229960004505 penfluridol Drugs 0.000 title claims abstract description 48
- 238000013270 controlled release Methods 0.000 title claims abstract description 44
- 239000008188 pellet Substances 0.000 title claims abstract description 23
- 229920002732 Polyanhydride Polymers 0.000 title abstract description 23
- 238000002360 preparation method Methods 0.000 title abstract description 19
- MJRDZKSKNYIAHZ-WLHGVMLRSA-N (e)-but-2-enedioic acid;decanedioic acid Chemical compound OC(=O)\C=C\C(O)=O.OC(=O)CCCCCCCCC(O)=O MJRDZKSKNYIAHZ-WLHGVMLRSA-N 0.000 claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 21
- 229940079593 drug Drugs 0.000 claims abstract description 19
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 150000004676 glycans Chemical class 0.000 claims abstract description 3
- 239000002245 particle Substances 0.000 claims abstract description 3
- 229920001282 polysaccharide Polymers 0.000 claims abstract description 3
- 239000005017 polysaccharide Substances 0.000 claims abstract description 3
- 239000011248 coating agent Substances 0.000 claims description 33
- 238000000576 coating method Methods 0.000 claims description 33
- 230000003203 everyday effect Effects 0.000 claims description 6
- 239000004375 Dextrin Substances 0.000 claims description 5
- 229920001353 Dextrin Polymers 0.000 claims description 5
- 235000019425 dextrin Nutrition 0.000 claims description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- 239000003405 delayed action preparation Substances 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- 206010067484 Adverse reaction Diseases 0.000 abstract description 10
- 230000006838 adverse reaction Effects 0.000 abstract description 10
- 239000000843 powder Substances 0.000 abstract description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 abstract description 4
- 206010037218 Psychopathic personality Diseases 0.000 abstract description 4
- 229920002472 Starch Polymers 0.000 abstract description 4
- 229930006000 Sucrose Natural products 0.000 abstract description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 abstract description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 abstract description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 abstract description 4
- 235000019359 magnesium stearate Nutrition 0.000 abstract description 4
- 201000000980 schizophrenia Diseases 0.000 abstract description 4
- 239000008107 starch Substances 0.000 abstract description 4
- 235000019698 starch Nutrition 0.000 abstract description 4
- 239000005720 sucrose Substances 0.000 abstract description 4
- 230000003247 decreasing effect Effects 0.000 abstract description 2
- 238000012423 maintenance Methods 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 description 59
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 24
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 21
- 238000003756 stirring Methods 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
- 238000010438 heat treatment Methods 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- 239000001530 fumaric acid Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 12
- 238000001291 vacuum drying Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000002156 mixing Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000010992 reflux Methods 0.000 description 7
- 239000008187 granular material Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 238000005292 vacuum distillation Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 208000028017 Psychotic disease Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 206010044565 Tremor Diseases 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 206010001541 Akinesia Diseases 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 206010020852 Hypertonia Diseases 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 229920000805 Polyaspartic acid Polymers 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- 206010057570 Respiratory dyskinesia Diseases 0.000 description 1
- 206010038743 Restlessness Diseases 0.000 description 1
- 206010039424 Salivary hypersecretion Diseases 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 206010044074 Torticollis Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000001055 chewing effect Effects 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 208000010118 dystonia Diseases 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000018197 inherited torticollis Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 108010064470 polyaspartate Proteins 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 208000026451 salivation Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000000276 sedentary effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a polyanhydride pellet, a penfluridol long-acting controlled-release tablet and a preparation method thereof, wherein the penfluridol long-acting controlled-release tablet comprises the following components in percentage: 50-60% of pentafluridopolyanhydride pellets, 15-20% of starch, 10-16% of sucrose powder, 5-10% of polysaccharide, 0.2-1.0% of magnesium stearate and 1-3% of hydroxypropyl cellulose. The pentafluridopolyanhydride pellets are mixture particles of (fumaric acid-sebacic acid) polyanhydride [ P (FA-SA) ] (FA: SA is 0.25:1) and pentafluridol, and the weight percentage content of the pentafluridol is 15-25%. The invention has long-acting controlled release effect, is orally taken for 2 times per month, can greatly reduce adverse reaction of penfluridol, improve clinical curative effect, facilitate the maintenance of family treatment of the psychopath and reduce the hospitalization cost and other treatment costs of the psychopath by taking 2 tablets each time or increasing or decreasing according to the condition of an illness or following the medical advice. Compared with other clinical medicines for treating schizophrenia, the medicine has better economic applicability and better clinical effective rate.
Description
Technical Field
The present invention relates to formulations of penfluridol.
Background
Penfluridol is a clinically common antipsychotic, and currently clinically used oral long-acting sugar-coated tablets are usually taken orally 1 time per week, 1 to 3 tablets each time, and 20mg tablets each time. Has definite curative effect on various acute and chronic schizophrenia[1]Becoming one of the current mental department first-line antipsychotics.
However, the clinical application of the drug for decades shows that many psychiatric patients have various adverse reactions of different degrees, the common adverse reactions are ① extrapyramidal reactions, such as Parkinson syndrome symptoms of increased muscle tone, stiff face, slow movement, muscle tremor, salivation and the like, ② acute dystonia, such as compulsive mouth opening, tongue stretching, torticollis, respiratory dyskinesia and dysphagia, ③ sedentary disability, such as restlessness and repeated loitering, ④ delayed dyskinesia, such as oral-tongue-cheek triad symptoms, such as sucking, tongue licking, chewing and the like, the most common adverse reactions are tremor, akinesia, tachycardia and the like, the occurrence rate is higher than 40 percent, even a transient heart, liver and the like can be caused, once serious adverse reactions occur, the normal life of the psychiatric patients is greatly interfered, serious adverse reactions are relieved by suicide means, and the adverse reactions are not tedious, and the clinical application of more organs is reduced.
Disclosure of Invention
The invention aims to provide a pentafluridol polyanhydride pellet, a pentafluridol long-acting controlled release tablet and a preparation method thereof, which overcome the defects in the prior art and meet the requirements of clinical application.
The pentafluridopolyanhydride pellets are mixture particles of (fumaric acid-sebacic acid) polyanhydride [ P (FA-SA) ] (FA: SA is 0.25:1) and pentafluridol, wherein: the content of the penfluridol in percentage by weight is 15-25%, and the preferable content is 20%;
the terms:
"P (FA- -SA)" refers to (fumaric acid- -sebacic acid) polyanhydride;
"FA: SA ═ 0.25: 1" means fumaric acid: sebacic acid ═ 0.25:1, moles;
FA is english abbreviation for fumaric acid; SA is the english abbreviation for sebacic acid; FA: SA means fumaric acid to sebacic acid (weight ratio). P (FA- -SA) is in the sense of polymerization or multimerization, i.e.fumaric acid and sebacic acid polymers.
The penfluridol long-acting controlled-release tablet comprises the following components in percentage:
the sum of the percentages of the components is 100%.
Preferably, the penfluridol long-acting controlled-release tablet comprises the following components in percentage:
the sum of the percentages of the components is 100%.
Particularly preferably, the penfluridol long-acting controlled-release tablet comprises the following components in percentage:
the polysaccharide is selected from more than one of dextrin, microcrystalline cellulose or lactose;
preferably, the controlled release tablet further comprises a coating outside the controlled release tablet, wherein the preferred coating is Opadry coating powder, and the weight is increased by 3-4%;
in order to ensure the clinical effective rate and minimize the adverse reaction, the long-acting controlled release preparation which is orally taken for 2 times per month and ensures that the drug release is 3-7mg every day must be prepared;
calculated according to the lowest dosage (20 mg/week) of each week, the drug release is ensured to be more than 3mg per day, and long-acting controlled release tablets with 3.5mg per day can also be prepared, and the number of the tablets for taking the drug is adjusted according to individual difference of patients to achieve the purpose of effectively treating diseases.
In order to release 3.5mg per day, 52.5mg is released in 15 days. The obtained pentafluridol long-acting controlled-release tablet is prepared into 2 tablets, wherein each tablet contains 26.25mg of the main drug pentafluridol, the obtained pentafluridol micro-pill contains 25% of drug, and each tablet contains 105mg of the prepared pentafluridol micro-pill (containing 26.25mg of pentafluridol). The obtained tablet is taken 2 tablets each time and 2 times a month, which is equivalent to 3.5mg of penfluridol taken daily.
If the drug is expected to release 7mg of penfluridol every day, the drug can be taken for 4 tablets every time by taking the drug 2 times a month, and the ideal result can be obtained by adjusting the number of tablets taken clinically according to various symptoms and morbidity of the psychotic.
The preparation method of the penfluridol long-acting controlled-release tablet comprises the following steps:
(1) dissolving a bulk drug of the penfluridol in ethanol, heating (fumaric acid-sebacic acid) polyanhydride to be molten, then adding a penfluridol solution at 65-70 ℃, stirring and mixing at 70-75 ℃ for 20-40 minutes, carrying out vacuum distillation at 70-75 ℃ to remove ethanol, carrying out vacuum drying, cooling and solidifying, crushing, carrying out vacuum drying, and crushing again to obtain a penfluridol polyanhydride pellet;
(2) mixing starch, sucrose powder, dextrin and the pentafluridopolyanhydride pellets, adding ethanol with the volume concentration of 50%, granulating by adopting a method known in the art, adding magnesium stearate and hydroxypropyl cellulose, and tabletting to obtain the long-acting controlled release tablet of the pentafluridol;
the weight consumption of 50% of ethanol is 10-35% of that of the pentafluridopolyanhydride pellets;
further, the method also comprises the following coating steps:
heating Opadry coating powder and ethanol to 40 ℃, mixing to obtain a coating solution (A), and standing for later use;
in the coating liquid (A), the weight content of the Opadry coating powder is about 13 percent.
And then coating the long-acting controlled-release tablet of the penfluridol by using the coating solution (A) by adopting a known method, and increasing the weight by 3-4 percent to obtain the long-acting controlled-release tablet of the penfluridol.
Wherein: the preparation method of the poly (fumaric acid-sebacic acid) [ P (FA-SA) ] (FA: SA is 20: 80) comprises the following steps:
1. preparation of fumaric prepolymer (a):
heating fumaric acid to the internal temperature of 135-140 ℃ under the protection of nitrogen, and carrying out reflux reaction for 1-2 hours, preferably 1.5 hours;
after the reaction is finished, recovering a reaction solvent (mainly acetic anhydride and acetic acid generated by the reaction) by vacuum distillation, and drying in vacuum to obtain a fumaric acid prepolymer (A);
the molar ratio of fumaric acid to acetic anhydride is: 0.25 mol: 3.07 mol: 1: 12-13;
2. preparation of sebacic acid prepolymer (B):
carrying out reflux reaction on sebacic acid and acetic anhydride at the temperature of 135-140 ℃ for 30-50 minutes, preferably 40 minutes under the protection of nitrogen, and collecting sebacic acid prepolymer (B) from reaction products;
the molar ratio of sebacic acid to acetic anhydride is: 1.5 mol: 9.63 mol: 1: 6-7;
3. preparation of poly (fumaric acid — sebacic acid):
reacting the fumaric acid prepolymer (A) with the sebacic acid prepolymer (B) at 170-190 ℃ and preferably 180 ℃ for 80-100 minutes and preferably 90 minutes under vacuum, and collecting the [ P (FA-SA) ] (FA: SA is 20: 80) from a product of the reaction, wherein mp is about 70 ℃.
The molar ratio of fumaric acid prepolymer (a) to sebacic acid prepolymer (B) was 0.25: 1;
the invention prepares the penfluridol into the long-acting controlled release tablet which is taken twice per month, ensures that the drug is released by 7mg every day (can be prepared into long-acting controlled release preparation which is taken one or two tablets each time, and can also be taken a plurality of tablets each time according to the state of illness and individual difference), can greatly reduce the clinical adverse reaction of the drug and improve the clinical effective rate.
There are many kinds of medicinal polymer sustained and controlled release materials, such as polylactic acid, polyurethane, polyaspartic acid, liposome, etc., but none of them can be used for preparing oral controlled release tablets, and only fumaric acid-sebacic acid) polyanhydride can be used for preparing oral controlled release tablets.
Compared with other medicinal polymer controlled release materials, fumaric acid-sebacic acid) polyanhydride: 1. has excellent biocompatibility and surface corrosion; 2. can be used for preparing oral controlled release tablets, and can promote drug dissolution and bioavailability; 3. fumaric acid-sebacic acid) polyanhydride decomposes at zero-order kinetic rate (uniform decomposition), and is well suited for the preparation of controlled release tablets; 4. the preparation is simple, the reaction temperature and ingredients can be changed to change the performance of the polyanhydride, the preparation is very suitable for preparing the oral controlled release tablet, and other medicinal high molecular polymers do not have the characteristics.
The invention has the beneficial effects that:
the long-acting controlled release tablet has a long-acting controlled release effect, is orally taken for 2 times per month, is taken for 2 tablets each time, or is increased or decreased according to the state of an illness or is in compliance with medical advice, can greatly reduce the adverse reaction of the penfluridol, improve the clinical curative effect, facilitate the maintenance of the family treatment of the psychopath, and reduce the hospitalization cost and other treatment costs of the psychopath. Compared with other clinical medicines for treating schizophrenia, the medicine has better economic applicability and better clinical effective rate. The long-term application of the penfluridol can maintain the family treatment of the psychotic, and the effective rate is up to 100%.
Detailed Description
Example 1
Preparation of poly (fumaric-sebacic acid) [ P (FA-SA) ] (FA: SA 20: 80):
1. preparation of fumaric prepolymer (a):
29g (0.25mol) of fumaric acid is added into a 1000ml four-mouth reaction bottle provided with a mechanical stirrer, a thermometer, a reflux pipe, a heater, a vacuum pipe and an addition funnel, air in the reaction bottle is pumped out in high vacuum, after the vacuum is closed, nitrogen is slowly introduced to ensure that the pressure in the bottle is consistent with the atmospheric pressure, and the operation is repeated once again. 250ml of acetic anhydride (313.2g, 3.07mol) was added from a separatory funnel, and the mixture was heated with stirring to an internal temperature of 135 ℃ under nitrogen protection to reflux for 1.5 hours. After the reaction, the reaction solvent (mainly acetic anhydride and acetic acid generated by the reaction are distilled in vacuum, and the temperature in the distillation is controlled to be not higher than 80 ℃). After the distillation is finished, the fumaric acid prepolymer (A) is obtained by vacuum drying in a distillation flask and is sealed and placed at room temperature for standby.
2. Preparation of sebacic acid prepolymer (B):
adding 303g (1.5mol) of sebacic acid into a 3000ml four-mouth reaction bottle provided with a mechanical stirrer, a thermometer, a reflux pipe, a heater, a vacuum pipe and a feeding funnel, vacuumizing the reaction bottle at high vacuum, closing the vacuum, slowly introducing nitrogen to ensure that the pressure in the bottle is consistent with the atmospheric pressure, and repeating the operation once again. 909ml of acetic anhydride (982g, 9.63mol) was added to the separatory funnel, and the mixture was heated to an internal temperature of 135 ℃ under nitrogen protection with stirring (external temperature of about 160 ℃) and refluxed for 40 minutes. After the reaction, the reaction solvent (mainly acetic anhydride and acetic acid generated by the reaction are distilled in vacuum, and the temperature in the distillation is controlled to be not higher than 80 ℃). After the distillation, 600ml of dichloromethane was added, the reaction product was dissolved by heating with stirring to a slight reflux (40 ℃), cooled to room temperature with stirring, and filtered under reduced vacuum. The filtrate was added dropwise to 2500ml of a mixed solvent [ petroleum ether (60-90 ℃ C.): diethyl ether 1: 1(v/v) ] while stirring to precipitate, and a white solid was collected at an excess rate and added to 500ml of a mixed solvent [ petroleum ether (60-90 ℃ C.): diethyl ether 1: 1(v/v) ] and soaked overnight. Filtration, cake washing with a small amount of anhydrous ether, vacuum drying to constant weight to obtain sebacic acid prepolymer (A)386g, mp: the yield is 90 percent at the temperature of 48-50 ℃, and the mixture is sealed and placed at room temperature for standby.
3. Preparation of poly (fumaric acid — sebacic acid):
286g (1mol) of sebacic acid prepolymer was charged into the above 1000ml four-necked reaction flask equipped with fumaric acid prepolymer (A) (0.25mol), the air in the reaction flask was evacuated under high vacuum at ordinary temperature, and nitrogen gas was introduced, and this process was repeated two more times to ensure that the air in the reaction flask was removed. The mixture is stirred and heated to the external temperature of 180 ℃ under high vacuum, and the reaction is carried out for 90 minutes. The heating was stopped, the reaction mixture was cooled to below 70 ℃ under vacuum, the vacuum was stopped, 600ml of chloroform was added, and the mixture was heated under stirring to slightly reflux (65 ℃) to dissolve the reaction mixture. Cooled to about 40 ℃, and the chloroform solution is slowly poured into 1500ml of petroleum ether (60-90 ℃) to precipitate under stirring, filtered and washed by a small amount of ether. Vacuum drying at 50 deg.C to constant weight to obtain product: poly (fumaric acid — sebacic acid) [ P (FA-SA) ] (FA: SA ═ 0.25:1, mp: about 70 ℃.
The following examples all employ the pentafluridopolyanhydride of example 1.
Example 2
Prescription: (weight)
105g of the pentafluridopolyanhydride pellets contain 26.25g of pentafluridol.
Making into 1000 pieces, shallow arc die
The weight of each tablet is 189mg, and each tablet contains 26.25mg of penfluridol.
The preparation process comprises the following steps:
dissolving the bulk drug of the penfluridol in ethanol, heating (fumaric acid-sebacic acid) polyanhydride to be molten, then adding a 65 ℃ penfluridol solution, stirring and mixing at 70 ℃ for 40 minutes, carrying out vacuum distillation at 70 ℃ to remove ethanol, carrying out vacuum drying, cooling and solidifying, crushing, carrying out vacuum drying, and crushing again to obtain a penfluridol polyanhydride pellet;
1. and (3) granulating: according to the dosage in the formula, starch, sucrose powder (powdered sugar which is crushed and sieved by a sieve of 80 meshes), dextrin and the pentafluridol pellets are mixed evenly in sequence, 21g of ethanol with the volume concentration of 50 percent is added and mixed simultaneously to prepare a wet material, and the wet material is granulated by a sieve of 20 meshes. And (3) placing the prepared wet granules in an oven, ventilating and drying at 65 ℃ under normal pressure, controlling the water content of the dry granules to be 3.5%, collecting materials, and finishing granules by using a 20-mesh screen to obtain a material (G).
2. Tabletting:
and adding magnesium stearate and hydroxypropyl cellulose into the prepared material (G) according to the amount in the formula, fully and uniformly mixing, and tabletting to obtain the long-acting controlled release tablet plain tablets of the penfluridol.
3. Coating with a film coat:
① the coating solution is prepared by adding 100ml ethanol into a three-mouth reaction bottle equipped with a mechanical stirrer, a thermometer and a heater, stirring and heating to 40 deg.C, stirring rapidly to form a vortex, adding 12g of white stomach soluble Opadry coating powder (after adding within 5 min), stirring rapidly at about 40 deg.C for 45 min, stopping heating, sealing, stirring, cooling to room temperature to obtain coating solution A, and standing.
② coating operation, namely adding 1000 tablets of the prepared penfluridol long-acting controlled-release tablet plain tablets into a small-sized coating pan for experiment, heating to 40 ℃ by hot air, adjusting the rotating speed of the coating pan to be 20-30 r/min, and slowly spraying the prepared coating solution (A) (about 45 ml) to increase the weight of the penfluridol long-acting controlled-release tablet plain tablets by 3% (when coating is carried out, the tablet temperature is kept at about 40 ℃), after coating is finished, continuously drying by hot air, and discharging to obtain the white penfluridol long-acting controlled-release coating tablet.
Example 3
Prescription:
the total amount of the materials is 200g, 1000 pieces are manufactured, and the shallow arc punching die
The weight of each tablet is 200mg, and each tablet contains 26.25mg of penfluridol.
Example 4
Prescription:
357g in total, and making into 1000 tablets, shallow arc punch die with the diameter of 10mm, the tablet weight of 357mg, each tablet containing 52.5mg of penfluridol, taking 1-2 tablets each time after oral administration every half and a month, which is equivalent to taking 3.5-7mg of penfluridol each day, if a patient needs a larger amount, several tablets can be taken at one time to achieve good clinical effect.
The preparation process comprises the following steps:
dissolving the bulk drug of the penfluridol in ethanol, heating (fumaric acid-sebacic acid) polyanhydride to be molten, then adding a 65 ℃ penfluridol solution, stirring and mixing at 75 ℃ for 20 minutes, carrying out vacuum distillation at 75 ℃ to remove ethanol, carrying out vacuum drying, cooling and solidifying, crushing, carrying out vacuum drying, and crushing again to obtain a penfluridol polyanhydride pellet;
1. and (3) granulating:
according to the dosage of the formula, starch, sucrose powder (powdered sugar which is crushed and sieved by a sieve of 80 meshes), lactose, microcrystalline cellulose, dextrin, hydroxypropyl cellulose and the pellets of the pentafluridol are mixed evenly in sequence, 50g of 50 percent ethanol (v/w) is slowly added while mixing, and the mixture is prepared into wet materials which are granulated by a sieve of 20 meshes. Placing the prepared wet granules in an oven, ventilating and drying at 60 ℃ under normal pressure, controlling the water content of the dry granules to be 3.5%, collecting the materials, and finishing granules by using a 20-mesh screen to obtain a material (G).
2. Tabletting:
and adding magnesium stearate into the prepared material (G) according to the amount in the formula, fully and uniformly mixing, and tabletting to obtain the long-acting controlled release tablet of the penfluridol.
3. Coating with a film coat:
① the coating solution is prepared by adding 100ml ethanol into a three-mouth reaction bottle equipped with a mechanical stirrer, a thermometer and a heater, stirring and heating to 40 deg.C, stirring rapidly to form vortex, adding 12g white stomach-soluble Opadry coating powder into one part (adding within 5 min), stirring rapidly at about 40 deg.C for 45 min, stopping heating, sealing, stirring, cooling to room temperature to obtain coating solution (A), and standing.
② coating operation, namely adding 1000 tablets of the prepared penfluridol long-acting controlled-release tablet plain tablets into a small-sized coating pan for experiment, heating to 40 ℃ by hot air, adjusting the rotating speed of the coating pan to be 20-30 r/min, and slowly spraying the prepared coating solution (A) (about 45 ml) to increase the weight of the penfluridol long-acting controlled-release tablet plain tablets by 4% (when coating is carried out, the tablet temperature is kept at about 40 ℃), after coating is finished, continuously drying by hot air, and discharging to obtain the white penfluridol long-acting controlled-release coating tablet.
Example 5
Degradation experiment of poly (fumaric acid-sebacic acid) -containing pentafluride anhydride:
the water content of the prepared pellet is less than or equal to 2 percent, the content of pentafluride is 25 percent, and the granularity is less than or equal to 80 meshes
The pellets of pentafluridol (fumaric acid- -sebacic acid) polyanhydride of example 1 were compressed using an infrared spectroscopy tableting die to form (20MPa, room temperature, 3min) discs (185mg,
about 1mm in thickness), two pieces were placed in 50ml of isotonic phosphoric acid having pH7.4In the salt buffer solution, degrading in a constant temperature oscillator at 37 ℃, changing the buffer solution every day, taking out the sample after n days, washing the sample with distilled water, drying in vacuum and weighing, wherein the degradation condition is expressed according to the mass loss of the sample, and the calculation formula is as follows:
the experimental results are shown in the following table:
the data show that the pentafluridol (fumaric acid-sebacic acid) polyanhydride pellets degrade at a rate of about 3.5% per day, which is enough to prove that the pentafluridol (fumaric acid-sebacic acid) polyanhydride pellets have a good controlled release effect. Description of the drawings: pH7.4 isotonic phosphate buffer [0.01mol/L, pH7.4(PBS) ] formulation:
the formula is as follows: 8g of sodium chloride, 0.2g of potassium dihydrogen phosphate and 12H of disodium hydrogen phosphate2O 2.9g，
0.2g of potassium chloride.
Preparation operation:
adding 500ml of water into a 1000ml quantitative bottle, sequentially adding the water according to the formula by shaking, fully shaking and dissolving the mixture completely, adding water to about 960ml, adjusting the pH to 7.4, adding water to the scale, and sterilizing the mixture under high pressure to obtain isotonic phosphate buffer solution with the pH of 7.4. Storing in a refrigerator at 4 deg.C for use.
Example 6
The pellets of pentafluridol (fumaric acid- -sebacic acid) polyanhydride of example 2 were subjected to the test in the same manner as in example 3, and the results were as follows:
the experimental results are shown in the following table:
the data show that (two experiments are taken, the weight of the material is about 714 mg) the pentafluridol (fumaric acid-sebacic acid) polyanhydride pellets degrade at a rate of about 3.5% every day, which is enough to prove that the pentafluridol (fumaric acid-sebacic acid) polyanhydride pellets have good controlled release effect.
Claims (5)
1. The penfluridol long-acting controlled-release tablet is characterized by comprising the following components in percentage:
the sum of the percentages of the components is 100 percent;
the pentafluridopolyanhydride pellets are mixture particles of poly (fumaric acid-sebacic acid) [ P (FA-SA) ] and pentafluridopolyanhydride, wherein FA: SA = 0.25:1, and the weight percentage content of the pentafluridopolyanhydride is 15-25%;
the polysaccharide is selected from more than one of dextrin, microcrystalline cellulose or lactose.
2. The penfluridol long-acting controlled-release tablet according to claim 1, which is characterized by comprising the following components in percentage:
the sum of the percentages of the components is 100%.
3. The penfluridol long-acting controlled-release tablet according to claim 1, which is characterized by comprising the following components in percentage:
4. the controlled release tablet of pentafluridol according to any one of claims 1 to 3, further comprising a coating on the controlled release tablet of pentafluridol.
5. The penfluridol long-acting controlled-release tablet according to claim 4, which is prepared into a long-acting controlled-release preparation orally taken 2 times per month to ensure that 3-7mg of drug is released every day, wherein each long-acting controlled-release tablet of the penfluridol contains 26.25mg of main drug of the penfluridol.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101134012A (en) * | 2006-08-30 | 2008-03-05 | 王永峰 | Method for producing injectable drug administration preparations using mixed polyacid anhydride as the carrier for middle-size or small molecule medicament and application thereof |
| CN101732311A (en) * | 2009-12-15 | 2010-06-16 | 苏春华 | Penfluridol-containing oral preparation and application thereof |
| CN104546784A (en) * | 2014-12-31 | 2015-04-29 | 康普药业股份有限公司 | Penfluridol tablet composition and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101134012A (en) * | 2006-08-30 | 2008-03-05 | 王永峰 | Method for producing injectable drug administration preparations using mixed polyacid anhydride as the carrier for middle-size or small molecule medicament and application thereof |
| CN101732311A (en) * | 2009-12-15 | 2010-06-16 | 苏春华 | Penfluridol-containing oral preparation and application thereof |
| CN104546784A (en) * | 2014-12-31 | 2015-04-29 | 康普药业股份有限公司 | Penfluridol tablet composition and preparation method thereof |
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